Hypoxia is the absence or shortage of oxygen in tissues. Hypoxia leads to tissue morbidity and even death. Humans have evolved a hypoxia adaptive response, to reductions in the O2 transport capacity of blood caused by blood loss or anemia. The reduced O2 transport capacity of blood in these situations can be partially compensated by a decrease in Hb-O2 affinity, which under normoxia increases O2 unloading to tissue without reducing O2 uptake in the lungs. The decreased Hb-O2 affinity is mediated by an increase in the red-cell 2,3-diphosphoglycerate concentration (DPG), a decrease in the pH of blood (Bohr Effect), and an increase in CO2 (Haldane Effect). This response is appropriate for blood loss or anemia, but is maladaptive for hypoxia caused by other clinical conditions.
Clinically, hypoxic conditions result from apneas, sleep apneas, impaired respiration, high altitude, hemoglobin mutations, blood loss, anemia and inadequate delivery of oxygen by a therapeutic oxygenation device. Other condtions that cause impaired respiration include respiratory diseases, pulmonary infections, asthma, pneumonia, interstitial lung disease, heart attack, stroke, congestive heart failure, unstable angina, drowning, multiple organ failure, reperfusion injury, pulmonary hypertension, pulmonary embolism, brain embolism, peripheral artery disease, deep vein thrombosis that leads to a clot in the lung, trauma, chronic obstructive pulmonary disease, sickle cell disease, chronic breathlessness, chronic obstructive pulmonary disease, bronchiectasis, valvular heart disease, left and/or right ventricular failure, motor neurone disease, obesity, anxiety, end-stage cancer and lung cancer. The primary treatment for hypoxia is the use of a therapeutic oxygenation device to deliver higher levels of oxygen in the inspired air or the use of a drug or medical device that directly reverses the cause of the impaired respiration, such as an antibiotic to treat pneumonia or a bronchodilator for the treatment of asthma.
5-hydroxymethyl-2-furfural (5-HMF) is being developed as a therapeutic treatment for sickle cell disease (SCD). U.S. Pat. No. 7,160,910 discloses therapeutic efficacy of 5-HMF in a murine model for SCD. Human clinical trials are being conducted under the auspices of the National Institutes for Health.
Abdulmalik et al., Br. J. Hematol. 128: 552-561 (2004) teaches that 5-HMF provides in vivo protection against the lethal effects of hypoxia in a sickle cell disease mouse model, and that this is the result of a lower P50 (left shift) in the SCD Hb, thus reducing the formation of sickled red blood cells in conditions of insufficient oxygen delivery from the inspired air. Thus, according to Abdumalik, the beneficial effect of 5-HMF in prolonging survival in the hypoxic state is due to the inhibition of RBC sickling, a phenomenon that is unique to SCD and would not be found in normal subjects.
Li et al., Cell Stress and Chaperones (published on-line Apr. 15, 2011) discloses a mouse model simulation of altitudinal hypoxia (hypobaric hypoxia) using a decompression chamber to simulate an altitude of 9,500 meters. 5-HMF was reported to increase survival of mice under these conditions. The authors attributed this to a partial blocking by 5-HMF of altitude-induced increases in permeability of blood brain barrier, thus protecting the brain from swelling and injury. According to this explanation, 5-HMF would be expected to be effective for treating only altitudinal hypoxia, and not other hypoxias that act other than by increasing the permeability zing of the blood brain barrier.
There is, therefore, a need for additional treatments for normal subjects who have hypoxia, other than altitudinal hypoxia.